Cytokine Storm: The Novel Mechanism for Sleep Deprivation-induced Multiple Organ Dysfunction Syndrome

It is well known that sleep is one of the inevitable activities of daily living and it is one of the most important factors contributing to human health. Sleep in mammals is a cyclic occurrence of two distinct states, rapid eye movement (REM) and non-rapid eye movement (NREM) [1]. Scientific guidelines for sleep suggest that 10 to 12 hours of sleep per night are appropriate for preschool children, 7 to 9 hours are appropriate for adults, and 7–8 hours are appropriate for elders [2]. Sleep is an essential component of cognitive health and physical development. During sleep, there are numerous changes to the body concerning its biological and physiological functions. The regulation of heart rate, blood pressure, hormonal secretion, temperature control, cellular repair, and immune defense functions all happen during sleep [3].

Sleep deprivation refers to abnormal sleep conditions that exhibit deficient sleep quantity, structure, and quality [4]. Currently, sleep deprivation seems to accompany the modern lifestyle, affecting all age groups as a global phenomenon. There are multiple factors contributing to sleep deprivation. Accumulating evidence supports that lifestyle factors such as night-shift work, stress, and the use of media and electronic devices before sleep contribute to the physiological alteration of melatonin secretion, which results in sleep deprivation [5, 6]. The aging process also disrupts sleep physiology and reduces the total sleep time [7].

There is a substantial amount of evidence on the adverse effects of sleep deprivation. Sleep deprivation is associated with higher health risks, including cardiovascular, respiratory, neurological, gastrointestinal, immunology, dermatology, endocrine, and reproductive health. Therefore, awareness of the adverse effects of sleep deprivation, which is often a neglected aspect should be emphasized [8].

Recently, Sang et al. reported prolonged sleep deprivation induces a cytokine-storm-like syndrome and MODS in mammals. Their findings elucidated that prolonged sleep deprivation regulates inflammation and results in serious adverse health effects [9].

Sang et al. first developed an efficient sleep deprivation mice model by placing mice in a shallow layer of water to prevent sleep. As the mice show signs of falling asleep, characterized by body curling, they are immediately awakened when their noses touch the water. This kind of sleep deprivation mouse model is named the “curling prevention by water (CPW) model”. Furthermore, they revealed that CPW leads to the deprivation of 95% of NREMS and 83% of REMS compared with the non-treatment group. CPW duration for 4 days results in 80% of sleep-deprived mice experiencing premature mortality and MODS including liver, spleen, lung, intestine, and kidney damage. All these results identified that prolonged sleep deprivation causes life-threatening MODS (Fig. 1).

Fig.1.

The specific molecular mechanism of cytokine storm and MODS induced by prolonged sleep deprivation. Prolonged sleep deprivation induces an accumulation of PGD₂ in the brain. ABCC4 subsequently promotes the efflux of PGD₂ across the brain-blood barrier (BBB), inducing excessive elevation of pro-inflammatory cytokine levels, ultimately leading to a cytokine-storm-like phenotype and MODS. Blocking the PGD₂/DP1 axis significantly reduces sleep deprivation-induced systemic inflammation and MODS.

Sang et al. further investigated the detailed molecular mechanism of prolonged sleep deprivation-induced-MODS. Prolonged sleep-deprived mice have suffered pathological cytokine storms, which are characterized by an increased concentration of proinflammatory cytokines. The majority of proinflammatory modulators are upregulated as sleep deprivation progresses. Notably, both IL-6 and IL-17A, which are two major contributors to cytokine storm in humans, are significantly upregulated as sleep deprivation progresses. Increased IL-17A further promotes serum levels of chemokine (C-C motif) ligand 20 (CCL20). Additionally, sleep deprivation enhances the proinflammatory factors chemokine (C-X-C motif) ligand 1 (CXCL1) and CXCL2 level, which contributes to neutrophil recruitment, and diapedesis. Here, they identified that cytokine storm mediates sleep deprivation-induced mortality and MODS.

To elucidate the effects of sleep deprivation on distinct cell populations, they performed a cell-type-specific transcriptome correlation analysis. Sleep deprivation causes the most dramatic changes in gene expression in neutrophils compared with other cell types. Circulating neutrophils accumulate and are activated during sleep deprivation. Moreover, neutrophils are depleted by intraperitoneal injection of anti-Ly6G antibodies. Neutrophil-depleted mice exhibit resistance to sleep deprivation-induced mortality compared with controls. They also analyzed the level of proinflammatory cytokines in neutrophil-depleted mice. However, circulating cytokines, particularly IL-6, still exhibit high levels in neutrophil-depleted mice. These findings suggested that neutrophils primarily function as major cellular effectors in contributing to sleep deprivation-induced mortality, rather than functioning as a source of cytokines.

Furthermore, Sang et al. revealed that the brain-derived PGD₂ participates in sleep deprivation-induced inflammation responses through ABCC4-mediated BBB efflux. They developed a characteristic detection PGD₂ fluorescence sensor, which can detect the fluctuations of PGD₂ levels in vivo and in vitro. By using this fluorescence sensor, they revealed that PGD₂ level is significantly increased in sleep-deprived mice compared with non-sleep-deprived mice. They further identified increased brain-derived PGD2 efflux across the BBB through ABCC4. They observed the brain efflux by using [³H]-labeled PGD₂. Sleep deprivation leads to a substantial increase in PGD2 efflux across the BBB. Moreover, the efflux of brain-derived PGD₂ is blocked in Abcc4^-/- mice, resulting in protection against sleep deprivation-induced mortality [10]

Finally, Sang et al. investigated whether blocking the PGD₂/DP1 axis could alleviate systemic inflammation during prolonged sleep deprivation. Prostaglandin D₂ synthase (PTGDS) is the main synthase of PGD₂. The level of PGD₂ and the release of neutrophil and serum IL-6 are inhibited in Ptgds^-/- KO mice stimulated by sleep deprivation compared with wild-type mice. Asapiprant, a DP1 antagonist, also can inhibit DP1-mediated signaling and significantly reduce the proportion of neutrophils among blood leukocytes stimulated by sleep deprivation. These results indicate inhibition PGD₂/DP1 axis could alleviate sleep deprivation-induced inflammation response.

Current research even identified that there is a bidirectional relationship between sleep deprivation and inflammation [11]. Sleep deprivation induces the release of pro-inflammatory factors. Moreover, prolonged sleep-deprived mice can induce intestinal flora imbalance, cause damage to the intestinal barrier, significantly increase serum endotoxin and corticosterone levels, and lead to the release of pro-inflammatory factors [12]. In return, pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 mediate circadian rhythm disruption and cause sleep fragmentation and sleep deprivation [12]. All these researches indicate the mutual interaction between sleep deprivation and inflammation.

Prevention of cytokine storms is critical for patients with prolonged sleep deprivation. However, inhibiting the complete array of proinflammatory cytokines might be very challenging. Compounds reducing the permeability of the BBB may be a more reasonable approach for the treatment. Sang et al. found that MK-571 inhibits PGD₂ efflux by inhibiting the permeability of the BBB, improving sleep deprivation-induced inflammation and MODS. Besides, folic acid (FA), Tong-Qiao-Huo-Xue Decoction (TQHXD), and ligustrazine can reduce the permeability of the BBB. All these compounds reducing the permeability of the BBB may serve as a plausible pharmacological development for treating adverse effects caused by sleep deprivation.

Conflict of interest

The authors declare that they have no conflict of interest.